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Working for tomorrow’s children: impact of antimicrobial resistance
on public health
Zulfiqar A. BhuttaHusein Lalji Dewraj Professor & Chair
Department of Paediatrics & Child HealthThe Aga Khan University
Where are 10 million children dying every year?Where are 10 million children dying every year?
Black et al 2003
Causes of death in children under 5CHERG Lancet (2005)
Time trends in estimates of ARI mortality
(in millions of deaths)
2.58
1.88 1.94
0
1
2
3
GBD 1990 CHERG 2000 GBD 2000
ARI burden of disease
• 5-9 episodes of ARI per year / U-5• 1 in 30-50 of these episodes are
pneumonia episodes (2-3% of all ARI)• In developing countries
– Most pneumonia is bacterial– Most ARI deaths are due to pneumonia
44%
41%
8% 7%
PneumoniaMeningitisSepsisOthers
Surveillance of invasive S. pneumoniaeClinical diagnosis
Duration of illness in children who died from pneumonia
Duration of illness before death is often short. Early maternal recognition of signs of pneumonia and prompt care seeking are essential to prevent deaths.
Average duration of symptoms of pneumonia before death was 3.5 days (Jumla, Nepal)
In young infants duration of illness was even shorter
Prescribing practices in childhood diarrhea Prescribing practices in childhood diarrhea (Nizami & Bhutta, Soc Sci Med 1996;42:1133) (Nizami & Bhutta, Soc Sci Med 1996;42:1133)
General Physicians PaediatriciansEncounters (n) 613 383Encounter time in minutes (SD) 3 (2) 9 (4)Antidiarrheals 59.7 % 28.5 %Antibacterials 66.1 % 50.0 %Antiamoebics 38.7 % 32.1 %Injectables 32.3 % 17.9%
Indiscriminate antibiotic use breeds resistance!Indiscriminate antibiotic use breeds resistance!
The Emergence of Penicillin Non-Susceptible Pneumococci in the U.S.
0%
10%
20%
30%
40%
50%
60%
1979 1981 1983 1985 1987 1990 1995 1998 2000
Worldwide Distribution of Penicillin Resistant Pneumococci
Brazil31%
Mexico53%
USA41%
South Africa80%
Saudi Arabia62%
Hong Kong80%
Israel54%
Japan64%
Singapore53%
Kenya49%
Russia7%
Canada14%
Worldwide S. pneumoniae Macrolide Resistance in 2000
Brazil4.0%
Mexico22%
USA33%
South Africa13%
Saudi Arabia18%
Hong Kong82%
Israel23%
Japan78%
Singapore55%
Kenya0.5%
Russia7%
Europe20%
Resistance defined as erythromycin MIC ≥1mg/L
Canada11%
RCTs non-severe pneumonia therapy
2% Cotrimoxazole (2 doses/d)1% Procaine penicillin (1 dose/d)
Keeley et al11987-88
Therapy regimen and failure rateRCTs
1. WHO Bull 1990;88-185, 2. Lancet 1998;352:270, 3. IUATLD 1997 321-PC04, 3. ADC 2002;86:113, 4. Lancet 2002; 360:835
20% 5-day amoxicillin thrice daily21% 3-day amoxicillin thrice daily
MASCOT5
1999-2000
19% Cotrimoxazole (2 doses/d)16% Amoxicillin (2 doses/d)
CATCHUP4
1998-99
17% Standard dose cotrimoxazole18% Double dose cotrimoxazole
COMET3
1995-96
12% Amoxicillin (3 doses/d)13% Cotrimoxazole (2 doses/d)
Straus et al 21991-92
Oral amoxicillin vs injectable penicillin in children with severe pneumonia9 centres in 8 countries n= 1702
Therapy failure
Penicillin (n = 845)
Amoxicillin(n = 857)
Total (%)
At 48 h
161 (19%)
167 (19%)
328 (19)
At 5 days
187 (22%) 186 (22%) 378 (22)
At 14 days 213 (25%) 225 (26%) 438 (25.7)
Amoxicillin Penicillin Pneumonia International Study (APPIS)Amoxicillin Penicillin Pneumonia International Study (APPIS)
Typhoid fever Typhoid fever is widely regarded as one of the most common causes of morbidity in the developing world. In South Asia, this is largely a paediatric diseaseS. typhi found to be most common cause of bacteremia among children dying with diarrhea at AKUMC.
Spectrum of paediatric blood culture isolates from AKUMCemergency services (1995-1999)
S. typhi (42.8%)Ambulatory care and emergency referral data may provide insight into the magnitude of the problem
S. paratyphi (8.3%)
Staph. epidermis (10.8%)
Others(18.2%)
Strep. spp. (8.3%%)
E.coli (2.7%)
The Study Sites
Karachi City
The sites were chosen as they are typical of conditions in slum areas of cities throughout Pakistan
SULTANABAD HIJRAT COLONY
1,00826225,982Bilal Colony
79537447,049Total
719689,458Sultanabad
3794411,609Hirjat Colony
Annual incidence per 100,000 population
Total Cases
2001 Population
Area
Incidence (Aug 2002 – July 2003 in Sultanabad and HirjatColony) and (Aug 2003 – July 2004 in Bilal Colony)
Incidence of culture proven typhoid fever 2-15 years old
Salmonella typhiSalmonella typhi
19881989
19901991
19921993
19941995
19961997
19981999
20002001
0
20
40
60
80
100
Multidrug Resistant Partially Drug Resistant Sensitive%
Antimicrobial use in Karachi Antimicrobial use in Karachi (units per 10,000 population) (units per 10,000 population)
19881989
19901991
19921993
19941995
19961997
19981999
20002001
0
500
1000
1500
2000
2500
3000
Ampicillin/Amoxicillin Chloramphenicol TXP-SX
Antimicrobial use in Karachi Antimicrobial use in Karachi (units per 10,000 population) (units per 10,000 population)
19881989
19901991
19921993
19941995
19961997
19981999
20002001
0.1
1
10
100
1000
Ceftriaxone Cefixime Ofloxacin/Ciprofloxacin Monobactams
Implications of growing antibiotic resistance
$84-104Parenteral cephalosporins (ceftriaxone)
$37-42Oral cephalosporins (cefixime)
$35-42Azithromycin
$24-30Prolonged fluoroquinolone treatment for quinolone or nalidixic acid resistant cases
$3-5Course of antibiotics for non-resistant cases
Source: AKU Pharmindex 2004 & WHO guidelines 2003
Average Treatment Costs for Typhoid (US$)Child weighing 20 kg using standard treatment
guidelines
Implications• Increasing antimicrobial resistance to
common organisms correlates closely with antimicrobial “pressure” and emergence of resistant strains
• Once established these drug resistant isolates are associated with higher rates of treatment failure and increasing cost of therapy
• The implications of these findings are much greater for health systems in developing countries